Cinnamamide derivative

ABSTRACT

Cinnamamide derivatives and the salts thereof are provided. An antihyperlipidemic composition is also provided. The composition comprises an active ingredient which is at least one selected from the group consisting of the above-mentioned cinnamamide derivative and the pharmaceutically acceptable salt thereof.

This is a divisional of co-pending application Ser. No. 07/548,121 filedon Jul. 5, 1990 now U.S. Pat. No. 5,294,643.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a cinnamamide derivative and the saltsthereof, which are novel compounds possessing antihyperlipidemicactivities in addition to being useful as intermediates for many otherorganic compounds; and an antihyperlipidemic composition orantiarteriosclerotic composition comprising the aforementioned substanceas an active ingredient.

2. Description of the Prior Art

Arteriosclerosis is one of the most widespread human diseases at thepresent time, and it is known that arteriosclerosis is one of the maincontributing factors in angina pectoris, myocardial infarction, cerebralinfarction and many other grave disorders. One of the principalcausative factors of arteriosclerosis is hyperlipidemia.

As is well known, serum lipid concentrations, particularly serumcholesterol levels, are very closely related with the occurrence ofarteriosclerosis. Serum cholesterol is classified into categories suchas LDL (i.e., low density lipoprotein) and HDL (i.e., high densitylipoprotein) . The presence of LDL-cholesterol promotes the depositionof cholesterol onto the arterial walls, however, HDL-cholesteroltransports excess cholesterol from the peripheral blood vessels andreturns this cholesterol to the liver, thereby preventing the depositionof cholesterol onto the arterial walls. Thus, the susceptibility of thearterial walls to the accumulation of cholesterol is governed by thetotal serum cholesterol concentration and by the ratio of LDL to HDL.Therefore, an antihyperlipidemic agent which serves to reduce serumcholesterol levels, particularly LDL-cholesterol levels, is an importantdesideratum in the medical field.

In general, in many cases antihyperlipidemic agents are administeredover a prolonged period, and are therefore required to be of highsafety. However, existing drugs in this category, for example,clofibrate, entail serious side effects such as liver damage, therefore,they are not adequately safe.

SUMMMARY OF THE INVENTION

The cinnamamide derivative of this invention, which overcomes theabove-discussed and numerous other disadvantages and deficiencies of theprior art, is of the formula I: ##STR1## wherein R¹ is selected from thegroup consisting of hydrogen; alkyl containing 1 to 8 carbon atoms;

    --(CH.sub.2).sub.n 1COAR.sup.3,

wherein R³ is --OH, --OR⁴ (R⁴ is alkyl containing 1 to 3 carbon atoms),--NHR⁵ (R⁵ is alkyl containing 1 to 3 carbon atoms), --NH(CH₂)_(n) 2--C₆H₅ (n² is an integer of 0 to 3) ##STR2## (R⁶ is pyridyl or phenyl, andn³ is an integer of 0 to 3), ##STR3## (R⁷ is alkyl containing 1 to 5carbon atoms), or --NHNH--C₆ H₅, and n¹ is an integer of 1 to 3;##STR4## wherein R⁸ is alkyl containing 1 to 5 carbon atoms, --(CH₂)_(n)4COOR¹⁰ (R¹⁰ is hydrogen or alkyl containing 1 to 3 carbon atoms, and n⁴is an integer of 1 to 3), --(CH₂)_(n) 50(n⁵ is an integer of 1 to 3),phenyl or hydroxyphenyl, and R⁹ is --OH, --OR¹¹ (R¹¹ is integer of 0 to3) , or --(CH₂)_(n) 11R¹⁸ (R¹⁸ is phenyl, pyridyl, pyrimidyl orbenzimidazolyl, and n¹¹ is an integer of 0 to 3), and n⁸ is an integerof 1 to 3;

    --(CH.sub.2).sub.n 12NHR.sup.19,

wherein R¹⁹ is ##STR5## (R²⁰ is hydrogen or alkyl containing 1 to 3carbon atoms), or --COR²¹ (R²¹ is pyridyl), and n¹² is an integer of 1to 3; ##STR6## wherein R²² is phenyl, hydroxyphenyl, and n¹³ is aninteger of 1 to 3; ##STR7## wherein R²³ is --OH or phenyl, and n¹⁴ is aninteger of 1 to 3; ##STR8## wherein R²⁴ is alkyl containing 1 to 3carbon atoms, phenyl, or --CN; ##STR9## wherein R²⁵ is ##STR10## (R²⁶ isphenyl or pyridyl, n¹⁶ is an integer of 1 to 3), --CONH(CH₂)_(n) 17R²⁷(R²⁷ is pyrrolidinyl substituted by alkyl containing 1 to 3 carbonatoms, or thiazolyl, and N¹⁷ is an integer of 0 to 3), or ##STR11## andn¹⁵ is an integer of 0 to 3;

    --(CH.sub.2).sub.n 18R.sup.28,

wherein R²⁸ is --CN, imidazolyl, thienyl, thienyl substituted by alkylcontaining 1 to 3 carbon atoms, ##STR12## (R²⁹ and R³⁰ are independentlyalkyl containing 1 to 3 carbon atoms), pyridyl, ##STR13## [R³¹ ishydrogen, halogen, --NO₂, --COOH, --COOR³³ (R³³ is alkyl containing 1 to3 carbon atoms), or --OR³⁴ (R³⁴ is alkyl containing 1 to 3 carbonatoms), and R³² is hydrogen or --OR³⁵ (R³⁵ is alkyl containing 1 to 3carbon atoms], ##STR14## (R³⁶ and R³⁷ are independently alkyl containing1 to 3 carbon atoms), indolyl, or ##STR15## (R³⁸ is pyridyl), and n¹⁸ isan integer of 0 to 3; ##STR16## wherein R³⁹, R⁴⁰ and R⁴¹ areindependently alkyl containing 1 to 3 carbon atoms; ##STR17## naphthyl;indanyl; tetralinyl; and

    --COR.sup.42

wherein R⁴² is alkyl containing 1 to 3 carbon atoms; and

R² is selected from the group consisting of hydrogen, alkyl containing 1to 5 carbon atoms, and --(CH₂)_(n) 19--C₆ H₅ (n¹⁹ is an integer of 1 to3); or

R¹ and R² may be linked together with the amide nitrogen to form a ringof ##STR18## which is selected from the group consisting of ##STR19##(R⁴³ is hydrogen or alkyl containing 1 to 3 carbon atoms), ##STR20##(R⁴⁴ is phenyl or pyridyl, and n²⁰ is an integer of 0 to 2), ##STR21##(R⁴⁵ is hydrogen or alkyl containing 1 to 3 carbon atoms, R⁴⁶ is phenylor pyridyl, and n²¹ is an integer of 0 to 2), and ##STR22## (R⁴⁷ isalkyl containing 1 to 5 carbon atoms).

This invention also includes salts of the said cinnamamide derivative.An antihyperlipidemic composition of this invention comprises an activeingredient which is at least one selected from the group consisting ofthe above-mentioned cinnamamide derivative and the pharmaceuticallyacceptable salt thereof.

Thus, the invention described herein makes possible the objectives of:

(1 ) providing a novel compound that possesses the functions of reducingLDL-cholesterol concentrations, and raising concentrations ofHDL-cholesterol, as well as being of high pharmacological safety; and

(2) providing an antihyperlipidemic composition comprising, as an activeingredient, the compound possessing the aforementioned superiorcharacteristics.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Representative examples of the compounds of the present invention areshown in Table 1.

    TABLE 1      Elementary analysis (%) C H N Compound  Molecular Melting point     Experimental Theoretical Experimental Theoretical Experimental Theoretica     l No.  formula (°C.) value value value value value value        R.sup.1 R.sup.2         1 CH.sub.2 CH.sub.3 H C.sub.19 H.sub.29     NO.sub.2 210-214 75.37 75.20 9.58 9.63 4.85 4.62 2 CH.sub.2 CH.sub.2     CH.sub.3 H C.sub.20 H.sub.31 NO.sub.2 189-192 75.39 75.67 9.99 9.84 4.26     4.41 3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H C.sub.21 H.sub.32 NO.sub.2     156-157 75.91 76.09 10.05 10.03 4.51 4.23 4 CH.sub.2 CH.sub.2 CH.sub.2     CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 C.sub.25 H.sub.41 NO.sub.2     179-180 77.63 77.47 10.07 10.67 3.42 3.61      5     ##STR23##      H C.sub.24 H.sub.39 NO.sub.2 178-181 77.37 77.16 10.34 10.52 3.41 3.75     6 CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 H C.sub.21 H.sub.31 NO.sub.2 168-169     69.59 69.77 8.60 8.65 3.71 3.88 7 CH.sub.2 CO.sub.2 H H C.sub.19     H.sub.29 NO.sub.2 223-225 68.72 68.44 8.25 8.16 3.97 4.20 8 CH.sub.2     CONH(n-Bu) H C.sub.23 H.sub.36 N.sub.2 O.sub.3 84-87 71.37 71.10 9.26     9.34 7.54 7.21 9 CH.sub.2 CONHCH.sub.2 C.sub.6 H.sub.5 H C.sub.26     H.sub.34 N.sub.2 O.sub.3 166-168 74.15 73.90 8.03 8.11 6.91 6.63  10      ##STR24##      H C.sub.27 H.sub.43 N.sub.2 O.sub.3 189-190 70.97 70.86 9.41 9.48 9.39     9.18      11     ##STR25##      H C.sub.30 H.sub.41 N.sub.3 O.sub.3 115-118 73.53 73.28 8.29 8.41 8.23     8.55      12     ##STR26##      H C.sub.28 H.sub.36 N.sub.4 O.sub.3 188-194 69.85 70.26 7.71 8.00 12.14     11.71  13 CH.sub.2 CH.sub.2 CH.sub.2 CO.sub.2 H n-Bu C.sub.25 H.sub.39     NO.sub.4 Oily liquid 71.51 71.89 9.27 9.41 3.63 3.36 14 CH.sub.2     CO.sub.2 C.sub.2 H.sub.5 n-Bu C.sub.25 H.sub.39 NO.sub.4 100-105 71.67     71.89 9.70 9.41 3.78 3.36      15     ##STR27##      n-Bu C.sub.26 H.sub.41 NO.sub.5 52-54 69.48 69.76 9.37 9.23 3.44 3.13     16      ##STR28##      n-Bu C.sub.34 H.sub.49 N.sub.3 O.sub.3 78-80 74.24 74.55 9.16 9.02 7.32     7.67      17     ##STR29##      n-Bu C.sub.32 H.sub.46 N.sub.4 O.sub.3 60-65 72.26 71.87 8.60 8.67     10.84 10.48  18 CH.sub.2 CONHNHC.sub. 6 H.sub.5 n-Bu C.sub.29 H.sub.41     N.sub.3 O.sub.3 161-165 72.99 72.61 8.50 8.62 9.18 8.76      19     ##STR30##      H C.sub.25 H.sub.39 NO.sub.4 148-151 71.57 71.89 8.96 8.41 3.03 3.36     20      ##STR31##      H C.sub.22 H.sub.31 NO.sub.6 102-103 65.27 65.16 7.74 7.71 3.27 3.45     21      ##STR32##      H C.sub.26 H.sub.33 NO.sub.3 110-111 70.88 71.04 7.73 7.57 3.27 3.19     22      ##STR33##      H C.sub.23 H.sub.31 NO.sub.3 240-241 70.39 70.56 7.39 7.34 3.41 3.29     23      ##STR34##      H C.sub.27 H.sub.35 NO.sub.4 74-76 74.36 74.11 7.81 8.05 3.53 3.20  24      ##STR35##      H C.sub.31 H.sub.43 N.sub.3 O.sub.4 102-105 71.71 71.37 8.39 8.31 8.42     8.06  25 CH.sub.2 CH.sub.2 OCH.sub.3 H C.sub.20 H.sub.31 NO.sub.3     148-150 71.74 72.03 9.18 9.37 4.53 4.20 26 CH.sub.2 CH.sub.2 OH n-Bu     C.sub.23 H.sub.39 NO.sub.3 122-123 73.43 73.56 9.89 9.93 3.91 3.73 27     CH.sub.2 CH.sub.2 OCONH(n-Bu) n-Bu C.sub.28 H.sub.46 N.sub.2 O.sub.4     138-141 70.52 70.85 9348 9.77 5.59 5.90      28     ##STR36##      n-Bu C.sub.29 H.sub.40 N.sub.2 O.sub.4 Oily liquid 72.83 72.47 8.27     8.39 5.48 5.83      29     ##STR37##      n-Bu C.sub.27 H.sub.39 NO.sub.3 102-104 70.39 70.09 7.76 7.84 2.34 2.72      30 CH.sub.2 CH.sub.2 OCH.sub.3 CH.sub.2 C.sub.6 H.sub.5 C.sub.27     H.sub.37 NO.sub.3 104-105 76.71 76.56 8.69 8.81 3.50 3.31  31 CH.sub.2     CH.sub.2 SH H C.sub.19 H.sub.29 NO.sub.2 S 160-161 68.29 68.03 8.86 8.71     3.81 4.18      32     ##STR38##      H C.sub.23 H.sub.33 N.sub.3 O.sub.2 S 130-133 66.72 66.48 8.27 8.01     10.45 10.11      33     ##STR39##      H C.sub.24 H.sub.32 N.sub.2 O.sub.2 S 88-93 69.44 69.33 7.97 7.82 6.46     6.99  34 CH.sub.2 CH.sub.2 SC.sub.6 H.sub.5 H C.sub.23 H.sub.33 NO.sub.2     S  99-100 73.04 72.96 8.12 8.08 3.30 3.40      35     ##STR40##      H C.sub.23 H.sub.28 N.sub.3 O.sub.2 S 160-161 66.69 66.80 7.64 7.56     10.01 10.16      36     ##STR41##      H C.sub.26 H.sub.33 N.sub.3 O.sub.2 S 110-114 68.77 69.15 7.53 7.37     9.67 9.31  37 CH.sub.2 CH.sub.2 SCH.sub.2 CO.sub.2 C.sub.2 H.sub.5 n-Bu     C.sub.27 H.sub.43 NO.sub.4 S 91-92 67.58 67.89 9.14 9.07 2.77 2.93  38      ##STR42##      n-Bu C.sub.28 H.sub.47 N.sub.3 O.sub.3 S 64-65 63.11 63.25 7.68 7.77     7.58 7.90      39     ##STR43##      n-Bu C.sub.27 H.sub.37 N.sub.3 O.sub.2 S 107-110 68.77 69.05 8.18 8.37     9.29 8.95      40     ##STR44##      H C.sub.28 H.sub.38 N.sub.2 O.sub.4 91-94 72.46 72.07 8.03 8.21 5.61     6.00  41 CH.sub.2 CH.sub.2 NH C.sub.6 H.sub.5 H C.sub.23 H.sub.34     N.sub.2 O.sub.2 112-113 76.25 76.10 8.59 8.69 7.31 7.10      42     ##STR45##      n-Bu C.sub.30 H.sub.42 N.sub.2 O.sub.2 109-112 72.45 72.84 8.7 8.56     5.28 5.66      43     ##STR46##      n-Bu C.sub.32 H.sub.46 N.sub.2 O.sub.4 113-116 7.81 73.53 8.69 8.87     5.00 5.36      44     ##STR47##      CH.sub.2 C.sub.6 H.sub.5 C.sub.32 H.sub.39 N.sub.3 O.sub.3 114-117     74.51 74.82 7.83 7.65 7.77 8.18      45     ##STR48##      H C.sub.23 H.sub.33 NO.sub.3 181-182 75.78 75.91 8.43 8.41 3.29 3.54     46      ##STR49##      n-Bu C.sub.29 H.sub.41 NO.sub.3 56-59 77.36 77.12 9.41 9.15 2.80 3.10     47      ##STR50##      n-Bu C.sub.24 H.sub.37 NO.sub.4 54-58 71.39 71.07 9.33 9.69 3.18 3.45     48      ##STR51##      H C.sub.25 H.sub.33 NO.sub.2 165-167 79.32 79.11 8.70 8.76 3.98 3.69     49      ##STR52##      H C.sub.25 H.sub.30 N.sub.2 O.sub.2 90-94 76.51 76.89 7.59 7.74 7.54     7.17      50     ##STR53##      H C.sub.30 H.sub.35 NO.sub.2 225-226 81.4 81.59 8.05 7.99 3.31 3.17  51      ##STR54##      n-Bu C.sub.39 H.sub.53 N.sub.3 O.sub.2 57-60 78.32 78.61 8.84 8.97 7.41     7.05      52     ##STR55##      n-Bu C.sub.32 H.sub.45 NO.sub.3 159-161 73.22 73.39 8.51 8.55 2.83 2.67      53     ##STR56##      n-Bu C.sub.33 H.sub.51 N.sub.3 O.sub.3 145-146 74.68 74.82 9.27 9.15     7.61 7.48      54     ##STR57##      n-Bu C.sub.31 H.sub.51 N.sub.3 O.sub.3 S 207-211 69.42 69.79 7.10 7.37     8.25 7.87      55     ##STR58##      n-Bu C.sub.32 H.sub.41 N.sub.3 O.sub.3 S 172-173 70.24 70.17 7.49 7.55     7.31 7.67  56 CH.sub.2 CH.sub.2 CH H C.sub.23 H.sub.23 N.sub.2 O.sub.2     182-185 73.41 73.13 8.37 8.59 8.28 8.53 57 CH.sub.2 C.sub.4 H.sub.5 H     C.sub.24 H.sub.31 NO.sub.2 164-165 78.75 78.86 8.61 8.55 3.68 3.84 58     CH.sub.2 CH.sub.2 C.sub.4 H.sub.5 H C.sub.25 H.sub.33 NO.sub.2 157-160     79.41 79.11 9.01 8.76 3.31 3.69      59     ##STR59##      H C.sub.24 H.sub.34 N.sub.2 O.sub.4 158-159 70.03 70.22 7.31 7.37 6.51     6.82      60     ##STR60##      H C.sub.24 H.sub.34 NO.sub.2 F 147-148 75.28 75.17 7.93 7.89 3.51 3.65     61      ##STR61##      H C.sub.24 H.sub.30 NO.sub.2 F 130-135 75.55 75.17 7.83 7.89 3.24 3.65     62      ##STR62##      H C.sub.25 H.sub.31 NO.sub.4 207-210 73.63 73.32 7.92 7.83 3.08 3.42     63      ##STR63##      H C.sub.27 H.sub.37 NO.sub.4 80-84 73.99 73.77 8.21 8.48 3.54 3.19  64      ##STR64##      H C.sub.23 H.sub.30 N.sub.2 O.sub. 2 190-191 75.21 75.37 8.23 8.25 7.78     7.64      65     ##STR65##      H C.sub.24 H.sub.32 N.sub.2 O.sub.2 139-140 75.81 75.75 8.39 8.48 7.51     7.36      66     ##STR66##      H C.sub.23 H.sub.33 N.sub.3 O.sub.2 178-181 71.89 72.02 8.58 8.67 10.73     10.96      67     ##STR67##      H C.sub.22 H.sub.29 NO.sub.2 S 170-171 70.82 71.13 7.77 7.87 3.53 3.77     68      ##STR68##      H C.sub.32 H.sub.47 NO.sub.3 217-220 77.53 77.84 9.82 9.60 2.47 2.84     69 CH.sub.2 CH(OCH.sub.3).sub.2 H C.sub.21 H.sub.33 NO.sub.4 162-163     69.48 69.39 9.20 9.15 3.67 3.85 70 CH.sub.2 CN n-Bu C.sub.23 H.sub.34     N.sub.2 O.sub.2 144-145 74.70 74.55 9.36 9.25 7.28 7.56 71 CH.sub.2     CH.sub.2 N(CH.sub.3).sub.2 n-Bu C.sub.25 H.sub.42 N.sub.2 O.sub.2     173-174 74.46 74.58 10.55 10.52 6.81 6.96 72 CH.sub.2 C.sub.6 H.sub.5     n-Bu C.sub.28 H.sub.39 NO.sub.2 128-130 79.63 79.76 9.41 9.32 3.10 3.32     73      ##STR69##      n-Bu C.sub.26 H.sub.26 N.sub.2 O.sub.3 166-169 76.74 76.43 9.17 8.88     7.06 6.86      74     ##STR70##      n-Bu C.sub.27 H.sub.30 N.sub.2 O.sub.2  98-103 77.08 76.73 9.28 9.06     6.19 6.63      75     ##STR71##      n-Bu C.sub.30 H.sub.40 N.sub.2 O.sub.2 77-79 78.49 78.22 8.63 8.75 6.40     6.08      76     ##STR72##      n-Bu C.sub.21 H.sub.39 NO.sub.2 94-96 73.21 73.43 8.78 8.90 3.42 3.17     77      ##STR73##      CH.sub.2 C.sub.6 H.sub.5 C.sub.30 H.sub.34 N.sub.2 O.sub.2 155-158     79.27 78.91 8.11 7.95 5.82 6.14      78     ##STR74##      CH.sub.2 C.sub.6 H.sub.5 C.sub.33 H.sub.38 N.sub.2 O.sub.2 145-146     80.24 80.12 7.65 7.74 5.49 5.66      79     ##STR75##      n-Bu C.sub.32 H.sub.40 N.sub.4 O.sub.2 141-142 73.72 73.80 9.34 9.29     10.92 10.76      80     ##STR76##      H C.sub.22 H.sub.33 NO.sub.4 196-197 70.51 70.37 8.77 8.86 3.84 3.73     81      ##STR77##      H C.sub.21 H.sub.29 NO.sub.4 138-140 70.01 70.17 8.30 8.13 3.66 3.90     82      ##STR78##      H C.sub.27 H.sub.35 NO.sub.2 186-187 80.02 79.96 8.71 8.70 3.23 3.45     83      ##STR79##      H C.sub.26 H.sub.33 NO.sub.2 120-121 79.58 79.75 8.60 8.50 3.43 3.58     84      ##STR80##      n-Bu C.sub.27 H.sub.43 NO.sub.4 114-115 72.43 72.77 9.68 9.76 3.36 3.14      85  COOH.sub.3 CH.sub.2 C.sub.6 H.sub.5 C.sub.26 H.sub.33 NO.sub.3     103-105 76.91 76.62 8.03 8.16 3.29 3.44      ##STR81##                 86      ##STR82##      C.sub.22 H.sub.33 NO.sub.2 163-166 76.58 76.92 9.44 9.68 4.39 4.08  87      ##STR83##      C.sub.21 H.sub.31 NO.sub.3 141-143 73.27 73.00 8.91 9.05 4.27 4.05  88      ##STR84##      C.sub.25 H.sub.40 N.sub.2 O.sub.2 189-190 75.12 74.95 10.21 10.07 7.25     6.99      89     ##STR85##      C.sub.25 H.sub.37 NO.sub.4 157-158 72.31 72.25 8.96 8.98 3.48 3.37  90      ##STR86##      C.sub.25 H.sub.37 NO.sub.4 164-165 72.17 72.25 9.02 8.98 3.45 3.37  91      ##STR87##      C.sub.23 H.sub.33 NO.sub.4 201-205 71.57 71.29 9.27 8.58 3.30 3.61  92      ##STR88##      C.sub.28 H.sub.38 N.sub.2 O.sub.2 158-159 77.25 77.38 8.88 8.81 6.17     6.45      93     ##STR89##      C.sub.26 H.sub.35 N.sub.3 O.sub.2 147-150 74.32 74.07 8.48 8.37 9.61     9.97

The cinnamamide derivatives I of the present invention form salts withbases. Furthermore, the cinnamamide derivatives of the present inventioncan also form salts with acids in the following cases.

(i) When R¹ is of the formula --(CH₂)_(n) 1COR³, wherein R³ is ##STR90##or --NHNHC₆ H₅. (ii) When R¹ is of the formula ##STR91## wherein R⁹ is##STR92## (iii) When R¹ is of the formula --(CH₂)_(n) 7COR¹², whereinR¹² is of the formula --COR¹⁴ (R¹⁴ is pyridyl).

(iv) When R¹ is of the formula --(CH₂)_(n) 8SR¹⁵, wherein R¹⁵ is##STR93## or --(CH₂)_(n) 11R¹⁸ (R¹⁸ is pyridyl, pyrimidyl, orbenzimidazolyl).

(v) When R¹ is of the formula --(CH₂)_(n) 12NHR¹⁹.

(vi ) When R¹ is of the formula ##STR94## wherein R²⁵ is ##STR95## or--CONH(CH₂)_(n) 17R²⁷ (R²⁷ is pyrrolidyl substituted by alkyl containing1-3 carbon atoms, or thiazolyl).

(vii) When R¹ is of the formula --(CH₂)_(n) 18R.spsp.28 ##STR96##wherein R²⁸ is imidazolyl pyridyl, or ##STR97## (viii) When R¹ and R²are linked together with the nitrogen atom of the amide group, forming aring of ##STR98## which is ##STR99##

The salts of cinnamamide derivatives of the present invention include,for example, the following.

(1) Salts with various metals, such alkaline metals, alkali earthmetals, or aluminum.

(2) Ammonium salts.

(3) Salts with organic bases such as methylamine, ethylamine,diethylamine, triethylamine, pyrrolidine, piperidine, morpholine,hexamethyleneimine, aniline or pyridine.

(4) Salts with organic acids such as formic acid, acetic acid,trichloroacetic acid, maleic acid, tartaric acid, methanesulfonic acid,benzenesulfonic acid, or toluenesulfonic acid.

(5) Salts with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfonic acid, or phosphoric acid.

(6) Salts with amino acids such as arginine, glutamic acid, orornithine.

When salts of the above types are to be contained in antihyperlipidemiccomposition, pharmaceutically acceptable salts are selected.

The cinnamamide derivatives of formula I of the present invention, canbe synthesized, for example, by either the first or second of thefollowing methods.

In the first method, the cinnamamide derivative I is obtained by areaction between a compound of formula II and a compound of formula III.##STR100## wherein R⁴⁸ is hydrogen, or alkyl containing 1-4 carbonatoms. ##STR101## wherein R¹ and R² are the same as those of formula I.

The reaction between the compound II and the compound III is conductedwithout a catalyst, in the presence of a dehydrating condensing agent ora base. The aforementioned dehydrating condensing agents applicable forthe present purpose include conventional dehydrating condensing agentssuch as dicyclohexylcarbodiimide, and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The applicable basesinclude, for example, metal alcoholares such as sodium methoxide, alkylmetal compounds such as butyllithium, or metal hydrides such as sodiumhydride. Alternatively, the compound of formula II can be converted toan acyl halide by means of a halogenating reagent such as phosphoruspentachloride or thionyl chloride. Then this acyl halide is allowed toreact with the compound of formula III, thereby obtaining the desiredcinnamamide derivative I.

Cinnamamide derivatives I in which R¹ is --(CH₂)_(n) 1COR³ (R³ is --OR⁴)can be hydrolyzed by conventional methods using an acid or basecatalyst, thereby obtaining a cinnamamide derivative having a carboxylicgroup, wherein R³ is hydroxyl. Furthermore, the derivative having acarboxyl group so obtained can be treated with NH₂ R⁵, NH₂ (CH₂)_(n) 2--C₆ H₅, ##STR102## or NH₂ NH--C₆ H₅, thereby obtaining a compoundwherein R₃ is --NHR⁵, --NH(CH₂)_(n) 2--C₆ H₅, ##STR103## or --NHNHC₆ H₅.In the above formulae, R⁵, N², R⁶ and R⁷ are the same as those offormula I.

Furthermore, in the case where R¹ is ##STR104## R⁸ is --(CH₂)_(n) ⁴ CO₂^(R).spsp.10 and R¹⁰ is alkyl with 1-3 carbon atoms, then thecinnamamide derivative can be hydrolyzed by conventional methods usingan acid or base catalyst, thereby obtaining a cinnamamide derivativehaving a carboxyl group, wherein R¹⁰ is hydrogen. In the case where R¹is ##STR105## and R⁹ is --OR¹¹, then the cinnamamide derivative canfurther be hydrolyzed by conventional methods using an acid or basecatalyst, thereby obtaining a cinnamamide derivative having carboxylgroup, wherein R⁹ is hydroxyl. Furthermore, the derivative having acarboxyl group obtained in this manner can be treated with ##STR106##thereby obtaining a compound wherein R⁹ is ##STR107##

Furthermore, in the case where R¹ is --(CH₂)_(n) 8SR¹⁵ and R¹⁵ is--(CH₂)_(n) 9COOR¹⁷, the cinnamamide derivative can be hydrolyzed byconventional methods using an acid or base catalyst, and the resultingcinnamamide derivative having a carboxyl group so obtained can betreated with 2-aminothiazole, thereby obtaining a derivative wherein R¹⁵is ##STR108##

In the case where R¹ and R² are linked together with the amide nitrogento form a ring of ##STR109## wherein R⁴³ is alkyl with 1-3 carbon atoms,then the cinnamamide derivative can be hydrolyzed by conventionalmethods using an acid or base catalyst, thereby obtaining a cinnamamidederivative having a carboxyl group, wherein R⁴³ is hydrogen.

In the case where R¹ and R² are linked together with the amide nitrogento form a ring of ##STR110## wherein R⁴⁵ is alkyl with 1-3 carbon atoms,then the cinnamamide derivative can be hydrolyzed by conventionalmethods using an acid or base catalyst, thereby obtaining a cinnamamidederivative having a carboxyl group, wherein R⁴⁵ is hydrogen.

In the second method, the aforementioned cinnamamide derivative I issynthesized by a Witrig reaction in which an aldehyde is allowed toreact with a ylide. In the reaction,3,5-di-tert-butyl-4-hydroxybenzaldehyde can be used as the aidehyde,and, for example, a compound of the following formula IV can be used asthe ylide. ##STR111## wherein R¹ and R² are the same as in formula I.

In addition to the compound of formula IV, ylides derived fromtrialkylphosphines or triarylarsines can be used for the presentpurpose.

Among the cinnamamide derivatives I, those such that R¹ is ##STR112##and R²⁵ is --CONH(CH₂)_(n) 17R²⁷, can be synthesized by the followingmethod. First, a compound in which R²⁵ is -CO₂ R⁴⁹ (wherein R⁴⁹ is alkylwith 1-3 carbon atoms) is obtained by either the first or second of theaforementioned methods, then this product is converted into thecorresponding carboxylic acid by hydrolysis with an acid or basecatalyst in the same manner as indicated above. The carboxylic acid soobtained is allowed to react with a pyrrolidylalkylamine or athiazolylalkylamine, thereby obtaining the desired cinnamamidederivative.

The cinnamamide derivatives of the present invention and thepharmaceutically acceptable salts of these compounds are effective asantihyperlipidemic agents, and, moreover, are of extremely low toxicitywith respect to the living body. This will be apparent from the resultsof the experiments to be described below. Antihyperlipidemic compositioncontaining these cinnamamide derivatives or their salts can beadministered either orally or parenterally. The aforementionedcomposition generally contains a suitable carrier (i.e., excipient).Such composition includes tablets, capsules, fine granules, syrups,suppositories, ointments, and injections. The aforementioned carrier isan organic or inorganic solid or liquid whichever is appropriate for thepreparation of the desired form of the composition suitable for oral orparenteral administration. Ordinarily, an inert pharmaceutical excipientis used for this purpose. These excipients include crystallinecellulose, gelatin, lactose, starch, magnesium stearate, talc, vegetableor animal fats or oils, gums, and polyalkyleneglycols, Theantihyperlipidemic composition of the present invention contains theaforementioned cinnamamide derivatives and/or their salts in aproportion ranging from 0.2% by weight to 100% by weight. Theantihyperlipidemic composition may also contain other drugs (includingantihyperlipidemic agents), provided that these other drugs do notdiminish the efficacy of the aforementioned cinnamamide derivativesand/or their salts. In such cases, the aforementioned cinnamamidederivatives or their salts need not necessarily be the principalingredients of the said preparation.

The antihyperlipidemic compositions of the present invention aregenerally to be administered at dosages such that the desired effectsare attained without the occurrence of any side effects. The specificdoses to be administered will vary according to factors such as theseverity of the illness and the age of the patient, and should bedetermined in accordance with the judgment of the attending physician inevery case. However, the aforementioned cinnamamide derivatives and/ortheir salts should be administered in doses within the range of 1 mg-5g, and preferably 3 mg-1 g for an adult per day. Thus, the administeredamount of the actual drug preparation, including the excipient, shouldordinarily be in the range of 10 mg-10 g, and preferably 20 mg-5 g.

EXAMPLES

The present invention will be explained with reference to the followingexamples.

Example 1 Synthesis of Compound 3 (hereinafter, compounds are numberedas in Table 1)

A solution of 2.95 g of 3,5-di-t-butyl-4-hydroxycinnamyl chloridedissolved in 10 ml of THF was added to a mixed solution of 2.19 g ofn-butylamine and 10 ml of THF under ice cooling, and the mixture wasagitated for 3 hours. Then, 100 ml of ether was added and the mixturewas washed twice with water . The organic layer was dehydrated withsodium sulfate, evaporated to dryness, after which recrystallizationfrom a mixed solvent of benzene and n-hexane yielded 1.5 g of thedesired Compound 3.

Example 2 Synthesis of Compound 6

First, 2.79 g of glycine ethyl ester hydrochloride, 3.9 ml oftriethylamine and 4.20 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to 140 ml of a dichloromethanesolution containing 5.52 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, andthe mixture was allowed to react for 5 hours at room temperature. Then,water was added to the reaction mixture and the mixture was extractedwith chloroform several times. The organic layers were combined, washedwith water and concentrated under reduced pressure. Then, a mixedsolvent of methylene chloride and n-hexane was added to the residue, and5.9 g of the desired Compound 6 was obtained by crystallization (yield75%).

Example 3 Synthesis of Compound 7

First, 722 mg of the Compound 6 obtained in Example 2 was dissolved in20 ml of methanol, 4.5 ml of a 1N aqueous solution of sodium hydroxidewas added to the mixture, and the mixture was allowed to react at roomtemperature for 3 hours. The reaction mixture was then poured onto icewater and acidified with dilute hydrochloric acid. After chloroformextraction, the chloroform layers were combined, dehydrated with sodiumsulfate, and then concentrated under reduced pressure. Ethyl acetate wasadded to the concentrate, and 460 mg of the desired Compound 7 wasobtained by crystallization (yield 69%).

Example 4 Synthesis of Compound 14

First, 14.0 g of glycine ethyl ester hydrochloride, 13.7 g of n-butylbromide and 14 ml of triethylamine were refluxed overnight in ethanol .Then, an aqueous solution of sodium bicarbonate was added to thismixture, which was then extracted with chloroform. The organic layer wasdehydrated and concentrated. The concentrate so obtained, together with16.6 g of 3,5-di-t-butyl -4-hydroxycinnamic acid, was added to 300 ml ofmethylene chloride. To this mixture, 8.4 ml of triethylamin and 12.6 gof 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride wereadded, and the mixture so obtained was allowed to react for 5 hours atroom temperature.

After washing with 300 ml of dilute hydrochloric acid, the reactionmixture was also washed with water and then concentrated under reducedpressure. The residue was subjected to column chromatography usingsilica gel as a carrier, eluted with chloroform, the fraction containingthe desired compound was collected, and the solvent was distilled off,thereby obtaining 8 g of the desired Compound 14 (yield

Example 5 Synthesis of Compound 15

First, 3.3 g of 3,5-di-t-butyl-4-hydroxycinnamic acid and 2.1 g ofN-butylserine methyl ester were dissolved in 50 ml of dichloromethane,then, 2.9 g of 1-ethyl-3-(3-dimethylaminopropyl )carbodiimidehydrochloride was added to the mixture, and the mixture so obtained wasallowed to react for 2 hours at room temperature. This reaction mixturewas washed twice with 50 ml of water and concentrated under reducedpressure. The concentrate was subjected to column chromatography usingsilica gel as a carrier, eluted with chloroform, the fraction containingthe desired compound was collected, and the solvent was distilled off,thereby obtaining 3.2 g of the desired Compound 15 (yield 62%) .

Example 6 Synthesis of Compound 16

First, 1.5 g of N-n-butyl-N-carboxymethyl-3,5-di-t-butyl-4-hydroxycinnamamide prepared byhydrolyzing Compound 14 with sodium hydroxide, together with 0.69 g ofN-benzylpiperazine, was added to 40 ml of dichloromethane. Then, 0.82 gof 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride was addedto the mixture so obtained and the mixture was allowed to react for 5hours at room temperature. After completion of the reaction, thereaction mixture was washed twice with water and concentrated underreduced pressure. The concentrate so obtained was subjected to columnchromathography using silica gel as a carrier, eluted with chloroformcontaining 2% methanol, the fraction containing the desired compound wascollected, and the solvent was distilled off, thereby obtaining 0.97 gof the desired Compound 16 (yield 46%).

Example 7 Synthesis of Compound 19

First, 3.91 g of L-leucine ethyl ester hydrochloride, 3.1 ml oftriethylamine and 4.20 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to 140 ml of a dichloromethanesolution containing 5.52 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, andthe mixture was allowed to react for 5 hours at room temperature. Then,water was added to the reaction mixture and the mixture was extractedwith chloroform several times. The organic layers were combined, firstwashed with dilute hydrochloric acid, and then with water and evaporatedto dryness under reduced pressure. The residue was subjected to columnchromathography using silica gel as e carrier, eluted with chloroform,the fraction containing the desired compound was collected, and thesolvent was distilled oEE, thereby obtaining 5.0 g of the desiredCompound 19 (yield 68%).

Example 8 Synthesis of Compound 21

First, 6.0 g of 3,5-di-t-butyl-4-hydroxycinnamic acid and 4,8 g of4-hydroxyphenylglycine methyl ester hydrochloride were suspended in 100ml of dichloromethane, and 4.5g of1-ethyl-3-(3-dimethyleminopropyl)carbodiimide hydrochloride end 6.0 mlof triethylamine were added to the mixture so obtained end the mixturewas allowed to react for 2 hours at room temperature. APter completionof the reaction, the reaction mixture wes washed with water endconcentrated to dryness. The residue was subjected to columnchromathography using silica gel as a carrier, eluted with chloroform,the Erection containing the desired compound was collected, and thesolvent was distilled off, thereby obtaining 7.6 g of the desiredCompound 21 (yield 83%).

Example 9 Synthesis of Compound 22

First, 2.0 obtained of the Compound 21 obtained in Example 8 wesdissolved 10 ml of ethanol, and 30 ml of 15% aqueous solution of sodiumhydroxide was added. This reaction mixture was then heated at 60° C. andallowed to react for 2 hours. After cooling, the mixture was adjusted topH 1 by the addition of 2N hydrochloric acid, and then extracted threetimes with 50 ml of chloroform. The organic layers were combined anddehydrated with magnesium sulfate, after which the solvent was distilledoff under reduced pressure. Then, benzene was added to the residue and1.5 g of the desired Compound 22 was obtained by crystallization (yield79%)

Example 10 Synthesis of Compound 24

First, 20 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 11.2 g of serinemethyl ester hydrochloride, 13.6 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 10 ml of triethylamine were added to300 ml of dichloromethane, and then the mixture was allowed to react for2 hours at room temperature. After completion of the reaction, thismixture was washed by addition of water, and the dichloromethane wasdistilled off under reduced pressure. The residue so obtained wasseparated and purified by column chromatography on silica gel usingchloroform as an eluent, thereby obtaining 9.3 g ofN-3,5-di-t-butyl-4-hydroxycinnamyl)serine methyl ester.

The 9.3 g of N-(3,5-di-t-butyl-4-hydroxycinnamyl)serine methyl esterobtained in the aforementioned process and 24.6 ml of 1N sodiumhydroxide were added to 90 ml of ethanol, and after mixing the mixturewas allowed to react for 8 hours at room temperature. After completionof the reaction, this mixture was acidified with 2N hydrochloric acid,and then, chloroform was added. After mixing, the chloroform layer wasseparated and washed with water, and then the chloroform was distilledoff under reduced pressure. The residue so obtained was separated andpurified by column chromatography on silica gel using achloroform-methanol 9:1 mixture as an eluent, thereby obtaining 8.5 g ofN-(3,5-di-t-butyl-4-hydroxycinnamyl)serine.

The 8.5 g of N-(3,5-di-t-butyl-4-hydroxycinnamyl)serine so obtained,3.91 ml of N-benzylpiperazine, and 4.7 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedto 20 ml of dichloromethane, and the mixture was allowed to react for 3hours at room temperature. After completion of the reaction, thismixture was washed by addition of water, and then dichloromethane wasdistilled off under reduced pressure. The residue so obtained wasseparated and purified by column chromatography on silica gel, usingchloroform containing 1% methanol as an eluent, thereby obtaining 2.3 gof the desired Compound 24 (yield 6.2%).

Example 11 Synthesis of Compound 26

First, 2.76 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 1.17 g ofN-n-butylethanolamine and 2.1 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to50 ml of dichloromethane, and the mixture was agitated for 3 hours atroom temperature. Then, the reaction mixture was poured into water andextracted with chloroform. The chloroform layer was dehydrated withanhydrous sodium sulfate and the solvent was distilled off under reducedpressure. The residue so obtained was separated and purified by columnchromathography on silica gel with chloroform containing 1% methanol,after which hexane was added to the residue and crystallization yielded1.40 g of the desired Compound 26 in the form of white crystals (yield37%).

Example 12 Synthesis of Compound 27

First, 1.9 g of Compound 26 prepared in Example 12 was dissolved in 50ml of benzene, 0.6 ml of n-butylisocyanate and one drop of triethylaminewere added in the solution, and the mixture was then allowed to reactfor 16 hours at 70° C. After completion of the reaction, the reactionmixture was cooled and concentrated under reduced pressure. Theconcentrate so obtained was subjected to column chromathography usingsilica gel as a carrier, eluted with chloroform, the fraction containingthe desired compound was collected, and the solvent was distilled off.Then, a mixed solvent of ethyl acetate and hexane was added to theresidue and 1 . 0 g of the desired Compound 27 was obtained bycrystallization (yield 42%).

Example 13 Synthesis of Compound 28

First, 2.6 g of Compound 26 was dissolved in 30 ml of pyridine, then 1.2g of Nicotinoyl chloride hydrochloride was added by small portions whileconducting a reaction for 10 minutes at room temperature, after whichthe reaction was continued for hours at 80° C. After completion of thereaction and cooling, 100 ml of chloroform was added, and the mixture soobtained was poured into 100 ml of cold water, which was then extractedthree times with 50 ml of chloroform. The organic layers were combinedand concentrated under reduced pressure, after which the concentrate wassubjected to column chromatography on silica gel and eluted withchloroform. The fraction containing the desired compound was collectedand the solvent was distilled off, thereby obtaining 2.2 g of thedesired Compound 28 (yield 67%).

Example 14 Synthesis of Compound 30

First, 4.0 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 2.4 g ofN-(2-methoxyethyl)benzylamine and 3.4 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to50 ml of dichloromethane and the mixture so obtained was allowed toreact for 2 hours at room temperature. Then, the reaction mixture waswashed with water and the solvent was distilled off under reducedpressure. The residue so obtained was subjected to columnchromathography on silica gel using chloroform as an eluent, thefraction containing the desired compound was collected, and the solventwas distilled off. A mixed solvent of benzene and hexane was added tothe residue, and 4.9 g of the desired Compound 30 was obtained (yield79.8%).

Example 15 Synthesis of Compound 31

First, 3.0 g of 3,5-di-t-butyl-4-hydroxycinnamic acid and 0.84 g of2-aminoethanethiol were dissolved in 50 ml of dichloromethane, 2.2 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added tothe solution so obtained and the mixture was allowed to react for 2hours at room temperature. After completion of the reaction, thereaction mixture was washed with 20 ml of water and evaporated todryness. The residue so obtained was subjected to column chromathographyusing silica gel as a carrier, eluted with chloroform, the fractioncontaining the desired compound was collected, and the solvent wasdistilled off. Then, the mixed solvent of benzen and n-hexane was addedto the residue and 0.6 g of the desired Compound 31 was obtained bycrystallization (yield 16%).

Example 16 Synthesis of Compound 33

First, 3.0 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 1.67 g of2-(4-pyridylthio)ethylamine hydrochloride, 2.2 g of1-ethyl-3-(3-dimethylaminopropyl )carbodiimide hydrochloride and 1.5 mlof triethylamine were added to 50 ml of dichlromethane and the mixtureso obtained was then allowed to react for 2 hours at room temperature.After completion of the reaction, the reaction mixture was washed withwater and dichloromethane was distilled off under reduced pressure. Theresidue was separated and purified by column chromathography on silicagel using chloroformmethanol (9:1) mixture as an eluent, therebyobtaining 1.78 g of the desired Compound 33 (yield 39.6%).

Example 17 Synthesis of Compound 34

First, 1.4 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 0.8 g of2-phenylthioethylamine, 1.1 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.7 mlof triethylamine were added to 50 ml of dichloromethane and the mixtureso obtained was then allowed to react for 2 hours at room temperature.After completion of the reaction, the reaction mixture was washed byaddition of water and dichloromethane was distilled off under reducedpressure. The residue so obtained was separated and purified by columnchromathography on silica gel using chloroform as an eluent, therebyobtaining 1.2 g of the desired Compound 34 (yield 56.1%) .

Example 18 Synthesis of Compound 36

First, 0.50 g of 2-(2-aminoethyl)mercaptobenzimidazole, 0.72 g of3,5-di-t-butyl-4-hydroxycinnamic acid, and 0.67 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedto 15 ml of dichloromethane and the mixture so obtained was then allowedto react for 2 hours at room temperature. After completion of thereaction, the reaction mixture was washed by addition of water anddichloromethane was distilled off under reduced pressure. The residue soobtained was separated and purified by column chromathography on silicagel using chloroform containing 1% methanol as an eluent, therebyobtaining 0.3 g of the desired Compound 36 (yield 25.6%).

Example 19 Synthesis of Compound 38

First, 5.53 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 4.4 g ofN-ethoxycarbonylmethylthioethyl-n-butylamine, and 4.0 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) wereadded to 100 ml of dichloromethane and the mixture was agitated for 3hours at room temperature. Then, this reaction mixture was poured intowater, and after chloroform extraction the chloroform layer wasdehydrated with anhydrous sodium sulfate and the solvent was distilledoff under reduced pressure. The residue so obtained was separated andpurified by column chromatography on silica gel with chloroform, afterwhich hexane was added and crystallization yielded 7.34 g of anN-ethoxycarbonylmethylthioethyl-N-n-butylcinnamamide derivative (yield79.5%) in the form of white crystals.

Then, 4.62 g of the cinnamamide derivative so obtained were dissolved in70 ml of methanol, and 30 ml of a 1N sodium hydroxide solution wasgradually added under ice cooling while stirring over a period of 1hour. The reaction solution was then restored to room temperature andstirring was further continued for 1 hour. Next, the pH of this solutionwas adjusted to a value below 3 by addition of 1N hydrochloric acid, andthe solution was extracted with chloroform several times. The chloroformlayers were combined and dehydrated with anhydrous sodium sulfate, afterwhich the solvent was distilled off under reduced pressure. The residueso obtained was separated and purified by column chromatography onsilica gel column with chloroform containing 5% methanol, therebyobtaining 4.16 g of N-carboxymethylthioethyl-N-n-butylcinnamamidederivative in an oily form (yield 92.5%).

Then, 1.05 g of the aforementioned N-carboxymethylcinnamamide derivativeobtained above together with 0.25 g of 2-aminothiazole and 0.5 g of WSCwas added to 50 ml of dichloromethane and the mixture was stirred for 5hours at room temperature. Then, this reaction solution was poured intowater and extracted with chloroform several times. The chloroform layerswere combined and dehydrated with anhydrous sodium sulfate, after whichthe solvent was distilled off under reduced pressure. The residue soobtained was separated and purified by column chromatography on silicagel with chloroform, thereby obtaining 1.05 g of Compound 38 in the formof an amorphous powder (yield 85%) .

Example 20 Synthesis of Compound 39

First, 2.76 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 2.11 g of2-(n-butylaminoethylthio)pyrimidine and 2.0 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedto 50 ml of dichloromethane and the mixture was agitated for 5 hours atroom temperature. Then, this mixture was poured into water and extractedwith chloroform. The chloroform layer was dehydrated with anhydroussodium sulfate and the solvent was distilled off under reduced pressure.The residue so obtained was separated and purified by silica gel columnchromathography with chloroform, thereby obtaining 3.68 g of the desiredCompound 39 in an oily form (yield 79%) .

Example 21 Synthesis of Compound 40

First, 2.5 g of 3,5-di-t-butyl-4-hydroxycinnamic acid and 2.1 g ofethyl-4-(2-aminoethylamino)benzoate were dissolved in 50 ml ofdichloromethane. Then, 1.9 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added tothe solution obtained above and the mixture was allowed to react for 2hours at room temperature. After completion of the reaction, thereaction mixture was washed with water and dichloromethane was distilledoff under reduced pressure. The residue so obtained was separated andpurified by column chromathography on silica gel using chloroform as aneluent, thereby obtaining 3.1 g of the desired Compound 40 (yield 6.4%).

Example 22 Synthesis of Compound 43

First, 8.1 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 7.7 g ofethyl-4-[2-(butylamino)ethylamino]benzoate and 6.0 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedto 100 ml of dichloromethane and the mixture so obtained was allowed toreact for 2 hours at room temperature. Then, the reaction mixture waswashed with water and dichloromethane was distilled off. The residue soobtained was subjected to column chromathography on silica gel usingchloroform as an eluent, the fraction containing the desired compoundwas collected, and the solvent was distilled off. A mixed solvent ofbenzene and hexane was added to the residue and 9.7 g of the desiredCompound 43 was obtained by crystallization (yield 63.8%) .

Example 23 Synthesis of Compound 44

First, 0.6 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 0.5 g ofN-(2-benzylaminoethyl)nicotinamide and 0.5 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedto 20 ml of dichloromethane and the mixture so obtained was allowed toreact for 3 hours at room temperature. Then, the reaction mixture waswashed with water and dichloromethane was distilled off under reducedpressure. The residue so obtained was subjected to columnchromathography on silica gel using chloroform as an eluent, thefraction containing the desired compound was collected, and the solventwas distilled off. Ethyl acetate was added to the residue and 0.55 g ofthe desired Compound 44 was obtained by crystallization (yield 56.1%).

Example 24 Synthesis of Compound 46

First, 7.0 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 3.0 g ofN-butylphenylglycinol were dissolved in 100 ml of dichloromethane. Then,5.4 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride wasadded to the solution obtained above and the mixture was allowed toreact for 2 hours at room temperature. After completion of the reaction,the reaction mixture was washed twice with 50 ml of water andconcentrated under reduced pressure. The concentrate was subjected tocolumn chromathography using silica gel as a carrier, eluted withchloroform, the fraction containing the desired compound was collected,and the solvent was distilled off, thereby obtaining 3.8 g of thedesired Compound 46 (yield 34 %).

Example 25 Synthesis of Compound 48

First, 1.4 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 0.64 ml of1-phenylethylamine and 1.2 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride weredissolved in 30 ml of dichloromethane and the solution was then allowedto react for 2 hours at room temperature. After completion of thereaction, the reaction mixture was washed with water and dichloromethanewas distilled off under reduced pressure. The residue was subjected tocolumn chromathography using silica gel as a carrier, eluted withchloroform, the fraction containing the desired compound was collected,and the solvent was distilled off. A mixed solvent of ethyl acetate andn-hexane was added to the residue and 1.4 g of the desired Compound 48was obtained by crystallization (yield 73.7%).

Example 26 Synthesis of Compound 51

First, 3.6 g of 3,5-di-t-butyl-4-hydroxycinnamic acid and 4.4 g ofN-4-(4-benzyl-1piperazinyl)benzylbutylamine were dissolved in 50 ml ofdichloromethane. Then, 3.0 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added tothe solution obtained above and the mixture was allowed to react for 2hours at room temperature. The reaction mixture was washed twice with 50ml of water and concentrated under reduced pressure. The concentrate wassubjected to column chromathography using silica gel as a carrier,eluted with chloroform, the fraction containing the desired compound wascollected, and the Solvent was distilled off, thereby obtaining 6.3 g ofthe desired Compound 51 (yield 82%).

Example 27 Synthesis of Compound 53

First, 13.8 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 10.9 g of ethylN-butyl-p-aminobenzoate and 11.0 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedto 300 ml of dichloromethane and the mixture was allowed to react for 3hours at room temperature. This reaction solution was then washed withwater and concentrated under reduced pressure. The concentrate soobtained was chromatographed on a silica gel column with chloroform asan eluent, the fraction containing the desired compound was collectedand the solvent was distilled off. Then, a mixed solvent of ethylacetate and hexane was added to the residue so obtained and 9.4 g ofN-butyl-N-p-ethoxycarbonylphenyl-3,5-di-t-butyl-4-hydroxycinnamamide wasobtained by crystallization (yield 39.2%) .

Then, 6.0 g of the aforementionedN-butyl-N-p-ethoxycarbonylphenyl-3,5-di-t-butyl-4-hydroxycinnamamide soobtained was dissolved in 20 ml of ethanol, 25 ml of 2N sodium hydroxidewas added to the solution, and a saponification reaction was conductedfor 4 hours at 80° C. After completion of the reaction, this reactionsolution was acidified by addition of 2N hydrochloric acid, after whichthe solution was extracted with chloroform several times. The chloroformlayers were combined and concentrated, then benzene was added and 3.1 gof N-butyl-N-p-carboxyphenyl-3,5-di-t-butyl-4-hydroxycinnamamide wasobtained by crystallization (yield 55.4%).

Next, 1.6 g of theN-butyl-N-p-carboxyphenyl-3,5-di-t-butyl-4-hydroxycinnamamide soobtained together with 0.5 ml of 2-aminomethyl-l-ethylpyrrolidine and0.8 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride wasadded to 20 ml of dichloromethane, and the mixture was allowed to reactfor 2 hours at room temperature. This reaction solution was then washedwith water and the dichloromethane was distilled off. The residue soobtained was subjected to column chromatography on silica gel usingchloroform as an eluent, the fraction containing the desired compoundwas collected and the solvent was distilled off. Then, a mixed ethylacetate-hexane solvent was added to the residue so obtained and 0.94g ofthe desired Compound 53 was obtained by crystallization (yield 47.0%) .

Example 28 Synthesis of Compound 55

First, 7.5 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 6.4 g ofN-butyl-p-ethoxycarbonylbenzylamine and 5.7 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedto 100 ml of dichloromethane, and the mixture was allowed to react for 2hours at room temperature. This reaction solution was washed with waterand the dichloromethane was distilled off. Then, 100 ml of 10% sodiumhydroxide and 50 ml of ethanol were added to the residue so obtained,and the mixture was allowed to react for 16 hours at room temperature.After completion of the reaction, this reaction solution was acidifiedby addition of 2N hydrochloric acid and the mixture was extracted withchloroform several times. The chloroform layers were combined, thesolvent was distilled off, and the residue so obtained was subjected tocolumn chromatography on silica gel using chloroform containing 5%methanol as an eluent. The fraction containing the desired compound wascollected and the solvent was removed by distillation, after whichbenzene was added to the residue so obtained and 7.6 g ofN-butyl-N-p-carboxybenzyl-3,5-di-t-butyl-4-hydroxycinnamamide wasobtained by crystallization (yield 60.6%).

Then, 3.3 g of theN-butyl-N-p-carboxybenzyl-3,5-di-t-butyl-4-hydroxycinnamamide obtainedabove, together with 0.7 g of 2-aminothiazole and 1.9 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, was addedto 50 ml of dichloromethane, and the solution was allowed to react for 2hours at room temperature. This reaction solution was washed with waterand the dichloromethane was removed by distillation. Then, the residueso obtained was subjected to silica gel column chromatography usingchloroform as an eluent, the fraction containing the desired compoundwas collected and the solvent was removed by distillation, after whichbenzene was added to the residue so obtained and 1.9 g of the desiredCompound 55 was obtained by crystallization (yield 50. 0%).

Example 29 Synthesis of Compound 57

First, 2.8 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, and 1.1 ml ofbenzylamine were dissolved in 50 ml of dichloromethane. Then, 2.1 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added tothe solution obtained above and the mixture was allowed to react for 2hours at room temperature. After completion of the reaction, thereaction mixture was washed twice with water and concentrated underreduced pressure. The concentrate was subjected to columnchromathography using silica gel as a carrier, eluted with chloroform,the fraction containing the desired compound was collected, and thesolvent was distilled off. A mixed solvent of ethyl acetate and hexanewas added to the residue, and 2.4 g of the desired Compound 57 wasobtained by crystallization (yield 66%).

Example 30 Synthesis of Compound 61

First, 2.2 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, and 1.0 g of3-fluorobenzylamine were dissolved in 50 ml of dichloromethane. Then,2.0 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride wasadded to the solution obtained above and the mixture was allowed toreact for 2 hours at room temperature. After completion of the reaction,the reaction mixture was washed twice with 50 ml of water and thesolvent was distilled off under reduced pressure. The residue wassubjected to column chromathography using silica gel as a carrier,eluted with chloroform, the fraction containing the desired compound wascollected, and the solvent was distilled off. A mixed solvent of ethylacetate and hexane was added to the residue and 1.7 g of the desiredCompound 61 was obtained by crystallization (yield 55%).

Example 31 Synthesis of Compound 62

First, 2.8 g of 3,5-di-t-butyl-4-hydroxycinnamic acid was dissolved in50 ml of dichloromethane, then 3.6 ml of thionyl chloride was added, andthe mixture was heated and refluxed for 1 hour. The reaction mixture wasthen left to cool, and then concentrated under reduced pressure. 50 mlof chloroform was added to the concentrate so obtained, and this wasdripped under ice cooling into a solution prepared by dissolving 1.5 gof 4-(aminomethyl)benzoic acid in a mixture of 10 ml of pyridine and 30ml of chloroform. After the dripping operation was completed, themixture was heated and refluxed for 1 hour. This reaction solution wasthen poured into 50 ml of water, after which the mixture was extractedwith 50 ml of chloroform three times. The chloroform layers werecombined and the solvent was distilled off under reduced pressure. Then,the residue was subjected to column chromatography using silica gel as acarrier, and eluted with chloroform containing 5% methanol. The fractioncontaining the desired compound was collected, and the solvent wasdistilled off. Dichloromethane was added to the residue so obtained, and0.9 g of the desired Compound 62 was obtained by crystallization (yield22%).

Example 32 Synthesis of Compound 65

First, 2.8 g of 3,5-di-t-butyl-4-hydroxycinnamic acid and 1.2 ml of2-(aminoethyl)pyridine were dissolved in 50 ml of dichloromethane. Then,2.1 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride wasadded to the solution obtained above and the mixture was allowed toreact for 2 hours at room temperature. After completion of the reaction,the reaction mixture was washed twice with 50 ml of water andconcentrated under reduced pressure. The concentrate was subjected tocolumn chromathography using silica gel as a carrier, eluted withchloroform, the fraction containing the desired compound was collected,and the solvent was distilled off. Ethyl acetate was added to theresidue and 2.2 g of the desired Compound 65 was obtained bycrystallization (yield 58%).

Example 33 Synthesis of Compound 66

First, 3.0 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, and 1.3 ml of1-(3-aminopropyl)imidazole were dissolved in 50 ml of dichloromethane.Then, 2.2 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added to the solution obtained above and the mixturewas allowed to react for 2 hours at room temperature. After completionof the reaction, the reaction mixture was washed with 20 ml of water andevaporated to dryness. The residue was subjected to columnchromathography using silica gel as a carrier, eluted with chloroformcontaining 1% methanol, the fraction containing the desired compound wascollected, and the solvent was distilled off. A mixed solvent of ethylacetate and hexane was added to the residue and 2.4 g of the desiredCompound 66 was obtained by crystallization (yield 58%).

Example 34 Synthesis of Compound 75

First, 1.38 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 1.0 g of3-(n-butylaminomethyl)indole and 1.0 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to50 ml of dichloromethane and the mixture so obtained was agitated for 3hours at room temperature. Then, the reaction mixture was poured intowater and extracted with chloroform. The chloroform layer was dehydratedwith anhydrous sodium sulfate and the solvent was distilled off underreduced pressure. The residue so obtained was separated and purified bysilica gel column chromathography with chloroform, thereby obtaining0.65 g of the desired Compound 75 in the form of an amorphous powder(yield 28.1%).

Example 35 Synthesis of Compound 77

First, 2.76 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 1.98 g of4-(benzylaminomethyl)pyridine and 2.0 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to50 ml of dichloromethane and the mixture so obtained was agitated for 3hours at room temperature. Then, the reaction mixture was poured intowater and extracted with chloroform. The chloroform layer was dehydratedwith anhydrous sodium sulfate and the solvent was distilled off underreduced pressure. The residue so obtained was separated and purified bysilica gel column chromathography with chloroform and then withchloroform containing 2% methanol, after which hexane was added andcrystallization yielded 2.71 g of the desired Compound 77 in the form ofwhite crystals (yield 59%).

Example 36 Synthesis of Compound 79

First, 5.6 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 5.3 g of1-[2-(butylamino)ethyl]-4-(2-pyridyl)piperazine and 4.0 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to50 ml of dichloromethane and the mixture so obtained was allowed toreact for 3 hours at room temperature. Then, the reaction mixture waswashed with water and dichloromethane was distilled off. The residue soobtained was subjected to column chromathography on silica gel usingchloroform as an eluent, the fraction containing the desired compoundwas collected, and the solvent was distilled off. A mixed solvent ofethyl acetate and hexane was added to the residue and 6.1 g of thedesired Compound 79 was obtained by crystallization (yield 58.7%).

Example 37 Synthesis of Compound 80

First, 3.5 g of 3,5-di-t-butyl-4-hydroxycinnamic acid and 1.5 g of2-aminoisobutyric acid methyl ester hydrochloride was suspended in 50 mlof dichloromethane. Then, 5.4 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1.8 mlof triethylamine were added to the suspension obtained above and themixture was allowed to react for 2 hours at room temperature. Aftercompletion of the reaction, the reaction mixture was washed with 20 mlof water and evaporated to dryness. The residue was subjected to columnchromathography using silica gel as a carrier, eluted with chloroform,the fraction containing the desired compound was collected, and thesolvent was distilled off. A mixed solvent of benzene and n-hexane wasadded to the residue and 1.24 g of the desired Compound 80 was obtainedby crystallization (yield

Example 38 Synthesis of Compound 81

First, 1.52 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 1 g of(±)-α-amino-α-butyrolactone hydrobromide and 1.16 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedto 50 ml of dichloromethane and the mixture so obtained was agitated for18 hours at room temperature. Then, the mixture was washed with water,the organic layer was dehydrated with anhydrous sodium carbonate, andthe solvent was distilled off under reduced pressure. The oily substanceso obtained was separated and purified by silica gel columnchromathography with chloroform containing 2% methanol, after whichrecrystallization from ligroin yielded 1.1 g of the desired Compound 81in the form of white crystals (yield 56%).

Example 39 Synthesis of Compound 83

First, 2.76 g of 3,5-di-t-butyl-4-hydroxycinnamic acid and 1.7 g of2-aminoindan hydrochloride were dissolved in 50 ml of dichloromethane.Then, 2.0 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride and 1.4 ml of triethylamine were added to the solutionobtained above and the mixture was allowed to react for 5 hours at roomtemperature. To the reaction mixture, water was added and the mixturewas extracted with chloroform several times. The organic layers werecombined, first washed with dilute hydrochloric acid, and then withwater, and evaporated to dryness under reduced pressure. The residue soobtained was subjected to column chromathography using silica gel as acarrier, eluted with chloroform, the fraction containing the desiredcompound was collected, and the solvent was distilled off. A mixedsolvent of ethyl acetate and n-hexane was added to the residue and 3.46g of the desired Compound 83 was obtained by crystallization (yield89%).

Example 40 Synthesis of Compound 86

First, 2.2 g of 3,5-di-t-butyl-4-hydroxycinnamic acid was dissolved in10 ml of THF and this solution was added to the mixture of 1.91 g ofpiperidine and 10 ml of THF under ice cooling. Then, the mixture soobtained was agitated for 4 hours. To this mixture, 100 ml of ether wasadded and the mixture was washed twice with water. The organic layer wasdehydrated with sodium sulfate and then evaporated to dryness. Theresidue was recrystallized from benzene, thereby obtaining 700 mg of thedesired Compound 86.

Example 41 Synthesis of Compound 89

First, 2.76 g of 3,5-di-t-butyl-4-hydroxycinnamic acid and 1.57 g ofethyl pipecolinate were dissolved in 70 ml of dichloromethane. Then, 2.1g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride wasadded to the solution obtained above and the mixture was allowed toreact for 5 hours at room temperature. After completion of the reaction,the reaction mixture was washed with water and evaporated to drynessunder reduced pressure. To the residue, ethyl acetate was added, and 3.3g of the desired Compound 89 was obtained by crystallization (yield80%).

Example 42 Synthesis of Compound 92

First, 2.76 g of 3,5-di-t-butyl-4-hydroxycinnamic acid and 1.71 g ofN-benzylpiperazine were dissolved in 70 ml of dichloromethane. Then, 2.1g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride wasadded to the solution obtained above and the mixture was allowed toreact for 3 hours at room temperature. After completion of the reaction,the reaction mixture was washed with water and evaporated to drynessunder reduced pressure. To the residue, ethyl acetate was added and 3.1g of the desired Compound 92 was obtained by crystallization (yield72%).

Example43 Synthesis of Compound 93

First, 2.76 g of 3,5-di-t-butyl-4-hydroxycinnamic acid and 1.63 g ofN-(α-pyridyl)piperazine were dissolved in 70 ml of dichloromethane.Then, 2.1 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added to the solution obtained above and the mixturewas allowed to react for 3 hours at room temperature. After completionof the reaction, the reaction mixture was washed with water andevaporated to dryness under reduced pressure. Ethyl acetate was added tothe residue so obtained, and 3.0 g of the desired Compound 93 wasobtained by crystallization (yield 71%) .

Example 44

First, 100 g of Compound 3, 55 g of lactose and 41 g of dry potatostarch were kneaded together with 20 ml of water, then the mixture waspressed through a 16-mesh screen and dried at 40° C., resulting ingranules. Then, the granules were uniformly mixed with 4 g of magnesiumstearate and compressed by the conventional method, thereby obtainingtablets. The weight of each tablet was 200 mg and each tablet contained100 mg of Compound 3.

Example 45

Using Compound 57 in place of Compound 3, tablets were prepared by thesame procedure as in Example 44. The weight of each tablet was 200 mgand each tablet contained 100 mg of Compound 57.

Example 46

Using Compound 61 in place of Compound 3, tablets were prepared by thesame procedure as in Example 44. The weight of each tablet was 200 mgand each tablet contained 100 mg of Compound 61.

Example 47

First, 196 g of the granules obtained by the same procedure as inExample 44 was mixed with 4 g of magnesium stearate. Then, hard capsules(No. 2) were charged with 200 mg aliquots of this mixture. Each of theresulting hard capsulated preparations contained 100 mg of Compound 3.

Example 48

Using Compound 57 in place of Compound 3, hard capsulated preparationswere prepared by the same procedure as in Example 47. Each of theresulting hard capsulated preparations contained 100 mg of Compound 57.

Example 49

Using Compound 61 in place of Compound 3, hard capsulated preparationswere prepared by the same procedure as in Example 47. Each of theresulting hard capsulated preparations contained 100 mg of Compound 61.

Example 50

    ______________________________________                                        Compound 3        10.0 g                                                      Lactose           85.0 g                                                      Crystalline cellulose                                                                            4.5 g                                                      Magnesium stearate                                                                               1.5 g                                                      ______________________________________                                    

The aforementioned ingredients were thoroughly mixed, thereby obtaininga powder containing 100 mg of Compound 3 per gram.

Example 51

Using Compound 57 in place of Compound 3, a powder containing 100 mg ofCompound 57 per gram was obtained by the same procedure as in Example50.

Example 52

Using Compound 61 in place of Compound 3, a powder containing 100 mg ofCompound 61 per gram was obtained by the same procedure as in Example50.

Experiment 1

Antihyperlipidemic effects of Compounds 1-93 listed in Table 1, preparedby the methods of Examples 1-43 or by similar methods, were evaluated inaccordance with the following protocol using Wistar rats.

Male Wistar rats (mean body weight 150 g) were divided into groups forthis experiment, each groups including six rats. The Wistar rats in eachgroup were fed ad libitum for 7 days a diet containing Chow CA-1(supplied by Clea Japan, Inc.) supplemented with 1.5% cholesterol. 0.5%cholic acid and 5% olive oil. Test compounds were suspended in a 2.5%(w/v) gum arabic solution and administered orally to the rats on the4th, 5th, 6th and 7th days in a volume of 3 ml/kg body weight.

After the final administration of the compounds, the animals were fastedovernight, and on the 8th day blood was taken from the inferior venacava under ether anesthesia, and the serum was obtained bycentrifugation.

Serum levels of total cholesterol (T-C) and HDL-cholesterol (HDL-C) weremeasured by enzymatic methods with a TC Kit-K (Nippon Shoji Kaisha,LTD.) and a HDL-C Kit-N (Nippon Shoji Kaisha LTD.), respectively. Theserum levels were also determined for the control group which receivedonly an aqueous gum arabic solution. The rate of change for each serumlevels was calculated by the following formula. ##EQU1##

The difference between the values of T-C and HDL-C were calculated, andthis difference was regarded as the sum of the levels of VLDL- (very lowdensity lipoprotein) and LDL-cholesterol, The rate of change for the sumof the levels of VLDL- and LDL-cholesterol was also calculated. Theresults are shown in Table 2. These results demonstrate that thecinnamamide derivatives of the present invention display excellentantihyperlipidemic efficacy.

                  TABLE 2                                                         ______________________________________                                                           Rate of change in                                          Compound                                                                              Dosage     cholesterol level (%)                                      No.     (mg/kg/day)                                                                              T-C     HDL-C  (T-C)-(HDL-C)                               ______________________________________                                         1      25         -12     30     -25                                          2      50         -17     25     -29                                          3      10         -30     61     -58                                          4      50         -10     20     -11                                          5      50         -30     42     -49                                          6      50         -30     10     -36                                          7      50         -33     23     -54                                          8      50         -10     22     -21                                          9      50         -20     92     -48                                         10      50         -28     37     -45                                         11      10         -34     25     -45                                         12      25         -43     34     -58                                         14      50         -35     10     -45                                         15      50         -43     48     -66                                         16      25         -32     114    -77                                         17      25         -19     33     -35                                         18      50         -36     13     -53                                         19      50         -37     15     -50                                         20      50         -45     17     -55                                         22      25         -18     114    -67                                         23      25         -36     119    -84                                         24      50         -47     14     -60                                         25      25         -17     23     -31                                         26      25         -37     108    -82                                         27      25         -29     39     -48                                         28      25         -35     95     -82                                         29      50         -44     126    -82                                         30      50         -42     69     -67                                         31      50         -31     55     -54                                         32      50         -38     63     -63                                         33      25         -31     75     -63                                         34      25         -40     116    -86                                         35      50         -22     15     -37                                         36      50         -10     207    -66                                         37      50         -23     50     -40                                         38      25         -37     33     -63                                         39      25         -22     39     -41                                         40      50         -31     44     -49                                         41      50         -15     27     -32                                         42      50         -32     10     -40                                         43      50         -47     12     -56                                         44      50         -35     11     -43                                         45      25         -26     76     -55                                         46      25         -14     15     -21                                         47      50         -27     96     -55                                         48      50         -40     139    -81                                         49      50         -57     43     -79                                         50      50         -46     13     -58                                         51      50         -29     80     -53                                         52      50         -38     10     - 47                                        53      50         -44     10     -50                                         54      50         -14     13     -17                                         55      50         -11     175    -17                                         56      50         -14     70     -36                                         57      10         -30     153    -77                                         58      10         -18     76     -51                                         59      10         -24     72     -54                                         60      10         -24     54     -48                                         61      10         -29     126    -77                                         62      50         -22     93     -56                                         63      50         -35     56     -59                                         64      25         -42     36     -70                                         65      25         -38     38     -62                                         66      50         -25     51     -45                                         67      50         -14     65     -34                                         68      50         -40     11     -50                                         69      25         -31     38     -50                                         70      25         -45     29     -68                                         71      50         -17     28     -28                                         72      25         -50     34     -81                                         73      50         -41     11     -54                                         74      25         -30     73     -68                                         75      25         -14     46     -30                                         76      25         -33     75     -61                                         77      25         -22     51     -44                                         78      50         -26     39     -40                                         79      50         -13     131    -45                                         80      50         -47     13     - 61                                        81      50         -15     12     -31                                         82      50         -23     49     -51                                         83      25         -32     157    -89                                         84      50         -11     13     -19                                         85      50         -10     109    -24                                         86      50         -12     34     -27                                         88      50         -22     86     -49                                         89      50         -11     42     -37                                         90      50         -10     11     -18                                         91      50         -15     10     -21                                         92      10         -24     21     -38                                         93      10         -15     39     -32                                         ______________________________________                                    

Experiment 2

Acute toxicity of Compounds 1-93 listed in Table 1 was evaluated usingddY mice in accordance with the following protocol.

Six male ddY mice weighing 27-30 g were used in each group. Thecompounds 1-93 were suspended in a 0.5% sodium carboxymethylcellulosesolution and administered orally to the mice in a volume of 0.1 ml/10 gbody weight. For two weeks after the administration, general symptoms inthe animals were observed and deaths were checked. None of the compounds1-93 of the present invention induced deaths even when administered at adose of 500 mg/kg. As the results show, the values of LD₅₀ (50% lethaldose) for compounds 1-93 were estimated to be greater than 500 mg/kgindicating very low toxicity.

It is understood that various other modifications will be apparent toand can be readily made by those skilled in the art without departingfrom the scope and spirit of this invention. Accordingly, it is notintended that the scope of the claims appended hereto be limited to thedescription as set forth herein, but rather that the claims be construedas encompassing all the features of patentable novelty that reside inthe present invention, including all features that would be treated asequivalents thereof by those skilled in the art to which this inventionpertains.

What is claimed is:
 1. A cinnmamide derivative of formula I or a saltthereof: ##STR113## wherein R^(l) is selected from the group consistingof

    --(CH.sub.2).sub.n 1COR.sup.3,

Wherein R³ is ##STR114## (R⁶ is pyridyl or phenyl, and n³ is an integerof 0 to 3), or ##STR115## (R⁷ is alkyl having 1 to 5 carbon atoms) andn¹ is an integer of 1 to 3; ##STR116## Wherein R⁸ is ##STR117## (n⁶ isan integer of 1 to 3), and R⁹ is --OH, --OR¹¹ (R¹¹ is alkyl with 1 to 3carbon atoms); ##STR118## wherein R²⁵ is ##STR119## (R²⁶ is phenyl orpyridyl, n¹⁶ is an integer of 1 to 3), and n¹⁵ is an integer of 0 to 3;and

    --(CH.sub.2).sub.n 18R.sup.28,

Wherein R²⁸ is ##STR120## (R³⁸ is pyridyl), and n¹⁸ is an integer of 0to 3; R² is selected from the group consisting of hydrogen, alkyl having1 to 5 carbon atoms , and --(CH₂)_(n) 19--C₆ H₅ (n¹⁹ is an integer of 1to 3); or R¹ and R² may be linked together with the amide nitrogen toform a ring of ##STR121## which is selected from the group consisting of##STR122## (R⁴⁴ is phenyl or pyridyl, and n²⁰ is an integer of 0 to 2),##STR123## R⁴⁵ is hydrogen or alkyl having 1 to 3 carbon atoms, R⁴⁶ isphenyl or pyridyl, and n²¹ is an integer of 0 to 2), and ##STR124## (R⁴⁷is alkyl having 1 to 5carbon atoms).
 2. An antihyperlipidemiccomposition comprising an active ingredient of a cinnamamide derivativeand a pharmaceutically acceptable carrier, wherein said activeingredient is selected from the group consisting of a cinnamamidederivative of claim 3 or a pharmaceutically acceptable salt thereof.